During the last 2 decades, our laboratory was actively searching for the methods to reduce ischemic reperfusion injury during ischemic arrest. Unfortunately, many of the results, not only from our laboratory, but also from most of the laboratories, could not be translated for human patients, as it has become apparent from the failure of clinical trials. There might be several reasons for such failure; however, 1 of the reasons could be because of our lack of attention in recovery and healing process of the ischemically injured hearts. While most of our attention have always been directed towards the inhibition of ischemic injury, none of the studies paid any attention to the repairing or healing of the heart already subjected to ischemia/ reperfusion. Recent studies from our laboratory revealed that while ischemic/reperfusion certainly causes cellular injury, it also potentiates a repair mechanism, which does not become apparent because of massive tissue damage. To fill up this gap, we propose to examine the DNA and tissue repair process following the ischemic arrest and develop approaches to stimulate the healing process by addressing the following Specific Aims: i) by examining the role of VEGF in DNA and tissue repair by studying nucleotide excision repair (NER) process and PI-3-kinase/Akt signaling; ii) by studying the role of 2 major DNA repair proteins Ku 70/86 in post ischemic healing process; iii) by determining the role of Poly (ADP-ribose)polymerase (PARP-1) in DNA and tissue repair after ischemic/reperfusion injury; iv) by studying the methods to stabilize apurinic/apyrimidinic endonuclease (APE/Ref-1) system in the ischemic/reperfused heart in order to facilitate the repair process; and v) by examining the expression profiles of 2 DNA repair proteins Rad23 and Gadd45 in the ischemic/reperfused myocardium and determining the role of proeasome in the stabilization of these repair proteins and enhance the repair process. Stimulation of the repairing of the injured heart may open a new class of therapeutic agents, which could serve as powerful cardioprotective agents.